Differential immune responses behind different celiac disease manifestations

In celiac disease (CeD), dietary gluten serves as the driver for a comparatively well characterized small bowel mucosal immune response that generally results in small bowel mucosal villous atrophy and crypt hyperplasia along with a disease-specific transglutaminase 2 (TG2) targeting autoantibody response. Individuals with positive TG2 autoantibodies but normal small intestinal mucosal morphology are regarded at increased risk of developing CeD and represent patients with potential CeD. The removal of gluten from the diet leads to disappearance of the autoantibodies and normalization of the mucosal architecture in most cases. However, refractory CeD patients deviate from this dogma as they present with abnormal T cell compartment, persistent symptoms and villous atrophy despite a strict gluten-free diet. The heterogeneity of CeD presentation is further diversified by varying symptomatology. Gastrointestinal symptoms are the most canonical signs of CeD, and they include for instance diarrhea, vomiting, constipation and abdominal pain. Yet, a great portion of the patients manifest the disease at extraintestinal sites such as skin, musculoskeletal system or neuronal tissues. Beyond the involvement of various transglutaminase autoantibodies, the detailed immune mechanisms contributing to the development of these manifestations remains elusive, though. This review highlights the current understanding of the immunological differences in various manifestations of CeD. As the immunological basis of the different CeD phenotypes is at present insufficiently understood, more research on the subject is warranted before such data could be maximally applied to clinical practice.